Project Summary/Abstract As animals explore their environment, they encounter millions of chemical signals that must be correctly interpreted to identify food and mates and to avoid predation. In mammals, the majority of this chemical information is detected by the sensory neurons of the olfactory system, (OSNs), which express more than one thousand distinct olfactory receptors (ORs), specialized chemoreceptors that sense volatile, chemical odorants. While many of these receptors have been molecularly defined, how they function to elicit appropriate behavioral responses remains largely unclear (i.e., how does a mouse know to run away from a cat and toward a piece of cheese). This proposal outlines a series of experiments aimed at taking advantage of the opportunities offered by the olfactory system to begin to characterize the mechanisms by which chemosensory information is detected and processed to generate specific, stereotyped behavioral responses. We have recently identified a new family of olfactory receptors encoded by the Ms4a family of genes, which our preliminary experiments suggest are required to mediate innate avoidance responses to stimuli such as predator-derived odorants that signify danger to the animal. However, how MS4A receptors function to elicit these behaviors is largely unknown, which significantly impairs our understanding of how the olfactory system interprets relevant sensory stimuli to elicit appropriate behavioral responses. To begin to elucidate MS4A chemoreceptor function, in Aim 1 I will use mutagenesis, electrophysiology, and calcium imaging to determine how MS4As bind ligands and signal their presence. In Aim 2, I will use ex vivo and in vivo preparations as well as mouse behavioral assays to determine the contribution of MS4As to transducing predator odor presence into appropriate innate avoidance responses. Together, the experiments proposed here will characterize a novel family of odorant receptor and how it signals the presence of ethologically relevant odors. Broadly speaking, these studies seek to illuminate basic principles of olfaction, provide insight into mammalian chemosensation, and shed light on the neural pathways associated with sensory perception.